D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem....

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Hirsutene and Δ 9(12) –Capnellene D. P. Curran (1986) Presenter: Mehdi Moemeni

Transcript of D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem....

Page 1: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

Hirsutene and Δ9(12) –Capnellene

D. P. Curran (1986)

Presenter: Mehdi Moemeni

Page 2: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

Back Ground of Radical Structure

Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771.

C

In a modern context the first organic free radical identifiedwas triphenylmethyl radical. This species was discovered byMoses Gomberg in 1900 at the University of Michigan.

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Radical Reactions

Smith, M. B.; March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York:Wiley, ISBN 0-471-72091-7

Radical chain reactions have three distinct phases:1) initiation, 2) propagation, and 3) termination.

Initiation(heat or light)

Propagation

X2 2X

RH + X R + XH

R + X2 RX + X

Termination

R + X RX

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Baldwin’s Rules

YZ

X

YZ

X

YZ

X

YZ

X

YZ

X

YZ

X

Exo-Tet Endo-Tet Exo-Trig Endo-Trig

Exo-Dig Endo-Dig

- Tetrahedral for sp3 carbon- Trigonal for sp2 carbon- Digonal for sp carbon

Baldwin J. E. J. Chem. Soc., Chem. Commun. 1976, 18, 734.

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n-Bu3SnH

PhCO3t-Buh, (62%)

6-exo-trig

radicalcyclization

O

H Br

O

H

O

H

n-Bu3SnH

OO

Ketoneolefination

SativeneCopacamphene stereoisomeric ratio of 4 to 5 (2:3)

1 2 3

45

Bakuzis, P.; Campos, O.O.S.; Bakuzis, M. L.F. J. Org. Chem. 1976, 41, 3261.

Radical Reactions Examples

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Radical Reactions in Examples

Stork, G.; Sher, P.M.; Chen, H. L. J. Am. Chem. Soc. 1986, 108, 6384.

O

TBSO

I

OEt n-Bu3SnCl (0.1 equiv.),NaCNBH3 (2.0 equiv.),hTHF, 25 °C

C5H11

O

SiMe3

O

TBSO

OEt

5-exo-trig

radical cyclization

O

TBSO

OEt

intermoleculartrapping

O

TBSO

OEt

C5H11

O

SiMe3

n-Bu3SnH

O

TBSO

OEt

C5H11

O

SiMe3140 °C,

Brook Rearrangement

O

TBSO

OEt

C5H11

Me3SiO

2-(trimethylsilyl)-1-octen-3-one(7equiv.)

CO2H

HO

HO

HO H

H

H

6 7 8

91011

(+) prostaglandin F2

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Radical Reactions in Examples

Keck, G.E.; Yates, J.B. J. Org. Chem. 1982, 47, 3590;Keck, G.E.; Enholm, E.J.; Yates, J.B.; Wiley, M.R. Tetrahedron 1985, 41, 4079.

N

OOH

N

O

O

Br

N- bromosuccinimide

CH2Cl2, 0°C (83%)

N

O

O

BrSn n-Bu3

(2.0 equiv)

AIBN (cat.)PhH, reflux

(88%)

ON

O

intermoleculartrapping

ON

O

Sn n-Bu3(-n-Bu3Sn )-elliminationO

N

O

13 14 15

1617

NC NN CN

AIBN: 2,2’-azobisisobutyronitrile

Page 8: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

Radical Reactions in Examples

Barton, D.H.R.; Beaton, J.M.; Geller, L.E.; Pechet, M. M. J. Am. Chem. Soc. 1960, 82, 2640;Barton, D. H. R.; Beaton, J.M.; Geller, L.E.; Pechet, M.M. ibid. 1961, 83, 4076.Barton, D. H. R. Pure & Appl. Chem. 1968, 16, 1;Barton, D. H. R. Aldrichimica Acta 1990, 23, 3.

OH ClNO(nitrosyl chloride)

HONO h

HO H-atom

abstraction

OH

NO(nitric oxide)

OHN O

tautomerizationOHN OH

H3OOH OO

OH

18 19 20 21

222325 24

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Radical Reactions in Examples

Barton, D.H.R.; Beaton, J.M. J. Am. Chem. Soc. 1960, 82, 2641;Barton, D. H. R.; Beaton, J.M. ibid. 1961, 83, 4083.

HOH

H H

H

O

OAcO

corticosterone acetate

CINO

pyr., 25 °C

OH

H H

H

O

OAcO

NO

(-NO)hPhCH3, 32°C(nitrite ester photolysis)

OH

H H

H

O

OAcO

HOH

H H

H

O

OAcO

H-atom abstraction

2627

2829

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Radical Reactions in Examples

OH

H H

H

O

OAcO

HOH

H H

H

O

OAcO

H-atom abstraction

HOH

H H

H

O

OAcONO

tautomerization HOH

H H

H

O

OAcON

OH

O

H

H H

H

O

OAcOHO

(20% yield from SM)HNO2nitrous acid

NO

aldostrone 21-acetate

2829

3031

Barton, D.H.R.; Beaton, J.M. J. Am. Chem. Soc. 1960, 82, 2641;Barton, D. H. R.; Beaton, J.M. ibid. 1961, 83, 4083.

Page 11: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

Back Ground of Hirsutene

In 1947, Heatley and co-workers reported that (+)-hirsutic acid produced by the filamentousfungus Stereum hirsutum. This is derived, in vivo, from the (+)-hirsutene.

- First total synthesis : Nozoe, S; Tetrahedron Lett. 1976, 17, 195

- First total synthesis by Radical Reactions: Curran, D. P.; Rakiewicz, D. M. J. Am. Chem.Soc. 1985, 107, 1448Tetrahedron 1985, 41, 3943

- First Asymmetric total synthesis: Hua, D. H.; Sinai-Zingde, G,; Venkataraman, S.J. Am. Chem. Soc., 1985, 107, 4088.

H

H H

Hirsutene (a linear triquinane)

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Capnellene is a naturally occurring hydrocarbon derived from Capnella imbricata, a species ofsoft coral. Capnellene derivatives and hirsutenes, demonstrate antibacterial and antitumorproperties with pharmacological potential.

- First total synthesis: Paquette, L; J. Am. Chem. Soc. 1985, 107, 1448.

- First total synthesis by Radical Reactions : Curran, D.P.; Chen, M. H. Tetrahedron Lett. 1985,26,4991.

- First Asymmetric total synthesis: Meyers, A; Bienz,S; J. Org. Chem., 1990, 55,791.

Capnellene (a linear triquinane)

Back Ground of Capnellene

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Back Ground

Dennis Patrick CurranProfessor at University of Pittsburgh

Well known for work in the interface of radical chemistry and organic synthesis

Page 14: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

H

H H

Hirsutene

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Retrosynthetic Analysis and Strategy

Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107, 1448Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943

H

H Hhirsutene

H

H H

5-exo-dig

radicalcyclization H H

H

5-exo-trigradicalcyclization

H HH

I

H

C-C bondformation

SN2

lactoneopening

OO

H

THPO M

32

3334

35

36trans disubstituted cyclopentene

Page 16: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

Total Synthesis

O1- NaBH4, CeCl3(Luche reduction)

2- Ac2O, Et3N

OAcLDA, THF, -78°C

Then t-BuMe2SiClHMPA

O

OTBS

[3,3]CH3Cl, reflux

(Ireland ester enolateClaisen rearrangement)

O

OTBSH

PhSeCl, CH2Cl2, -78°C

Phenylseleno lactonizationO

PhSe

O

H2O2

THF(62% from 37)

O

OH

HH

SePh

O

37 38 39

4041

42

Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107, 1448Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943

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Total Synthesis

O

OH

HH

SePh

O

(Selenoxidesyn-elimination)

OO

H

THPO Br

Li naphthalenide, THF, -78°C(organolithium formation)

then CuBr SMe2(organocuprate formation)then 43(50-75%)

CO2H

HH

THPO

1. PPTS, EtOH2. LiAlH4(64% overall)

HH

HO

OH

1. (Tf)2OPyrCH2Cl2, -10°C

2. n-Bu4NIPhH, reflux(64% overall)

HH

I

I

HH

I 1. Me3Si Li(1.0 equiv)THF, 0°C

2. CsF(78% overall)

42

43

44

45

464748

Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107, 1448Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943

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Reductive Litiation

Freeman. J. Org. Chem. 1980, 45, 1294.

Br OTHPLi

LiBrNaphtalenide

OTHP

Li

OTHPLi

O

OH

CO2H

HH

THPO

45

Single regio and stereo isomer

Page 19: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

Total Synthesis

I

HH

n-Bu3SnH, AIBN (cat)

PhHreflux (80%)

HH

5-exo-trig

radical cyclizationHH

H

5-exo-digradical cyclization

HH

Hn-Bu3SnH

HH

H

()-hirsutene

48 49 50

51

Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107, 1448Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943

NC NN CN

AIBN: 2,2’-azobisisobutyronitrile

Page 20: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

Capnellene

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Retrosynthetic Analysis and Strategy

H

H H H

CO2HX

H H

H

OO

H

H

52 53

5455

Capnellene

5-exo-dig

radicalcyclization

5-exo-trig

radicalcyclization

Curran, D.P.; Chen, M. H. Tetrahedron Lett. 1985, 26,4991

Page 22: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

Total Synthesis

Curran, D.P.; Chen, M. H. Tetrahedron Lett. 1985, 26,4991

O()- norbornenone

Baeyer- villigeroxidation

OO

acid-catalyzedrearrangement

OH

H

O

MeMgBrCuBr.SMe2THF, -20°C

H

CO2H

Iodolactonization

I2OH

H

O

IDBU,THF, 25°C

(66% from 147)

OH

H

O

56 57

585960

Page 23: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

Acid catalyzed rearrangement

O

O

H

O

OH

HH

H

O

OH

H

O

H

H

O

Page 24: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

Total Synthesis

OO MgBr

CuBr.SMe2, THF, -20°C

(SN2 anti lactone opening)

O O

H

CO2HLiAlH4

(80% from 150)

O O

H

OH

1. MeSO2Cl2. NaI3. Li.H2N(CH2)2NH2

DMSO, 25°C(43% from 152)

O O

H

1. CrO3. aq. H2SO4, (CH3)2CO2. CH2N2( 70% overall)

H

CO2Me1. MeMgBr (excess)

2. Me3SiBr(90% overall)H

Br

OH

H

O

60 6162

636465

Jones oxidatio

Curran, D.P.; Chen, M. H. Tetrahedron Lett. 1985, 26,4991

Page 25: D. P. Curran (1986) - Home - Chemistry · Back Ground of Radical Structure Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771. C In a modern context the first organic free radical

Total Synthesis

Br

H

n-Bu3SnH, AIBN(cat.)

PhH80°C (80% GC yield) H

5-exo-trig

radicalcyclization H

H H

5-exo-digradicalcyclization

H

H Hn-Bu3SnH

H

H H

)-9(12)-Capnellene

65 66 67

68

Curran, D.P.; Chen, M. H. Tetrahedron Lett. 1985, 26,4991

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Conclusion

Through the application of radical chemistry, valuable functional group transformationsand challenging carbon-carbon bond construction can be achieved under usually mildreaction condition.

Radical reactions are powerful, one-pot strategies for the synthesis of complexpolycyclic molecules.

Carbon-centered radicals are also highly reactive intermediates that add to carbon-carbon π bonds via early, reactant-like transition states.

Tandem or sequential radical cyclizations can offer exceedingly concise solutions tochallenging problems in organic synthesis.